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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2022

Evolution and folding of repeat proteins

Résumé

Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. These proteins constitute excellent model systems to investigate how evolution relates to structure, folding, and function. Here, we propose a scheme to map evolutionary information at the sequence level to a coarse-grained model for repeat-protein folding and use it to investigate the folding of thousands of repeat proteins. We model the energetics by a combination of an inverse Potts-model scheme with an explicit mechanistic model of duplications and deletions of repeats to calculate the evolutionary parameters of the system at the single-residue level. These parameters are used to inform an Ising-like model that allows for the generation of folding curves, apparent domain emergence, and occupation of intermediate states that are highly compatible with experimental data in specific case studies. We analyzed the folding of thousands of natural Ankyrin repeat proteins and found that a multiplicity of folding mechanisms are possible. Fully cooperative all-or-none transitions are obtained for arrays with enough sequence-similar elements and strong interactions between them, while noncooperative element-by-element intermittent folding arose if the elements are dissimilar and the interactions between them are energetically weak. Additionally, we characterized nucleation-propagation and multidomain folding mechanisms. We show that the global stability and cooperativity of the repeating arrays can be predicted from simple sequence scores.

Dates et versions

hal-03854601 , version 1 (15-11-2022)

Identifiants

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Ezequiel Galpern, Jacopo Marchi, Thierry Mora, Aleksandra Walczak, Diego Ferreiro. Evolution and folding of repeat proteins. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119 (31), ⟨10.1073/pnas.2204131119⟩. ⟨hal-03854601⟩
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